Biodegradable polymers have been used for many years in medical applications. Medical devices made from biodegradable polymers include sutures, surgical clips, staples, implants, and drug delivery systems. The majority of these biodegradable polymers have been solid thermoplastic materials based upon glycolide, lactide, caprolactone, and copolymers thereof. Some of these biodegradable polymers are star-branched polymers, such as those disclosed in U.S. Pat. Nos. 5,922,338 and 5,922,682, which can be used in sustained release medical devices (U.S. Pat. Nos. 5,538,739; 5,639,480; and 5,688,530).
Placing medical devices such as implants and other solid articles in a body frequently involves a surgical procedure. An incision is made, for example, and the solid implant is positioned within a body at the site of the incision. In other variants, such as disclosed in U.S. Pat. No. 4,938,763 the biodegradable polymer is introduced in a body as a flowable formulation. In these examples, a solution of the biodegradable polymer and an organic solvent is injected into a body. Upon contact with aqueous or body fluid, the polymer coagulates, forming a solid implant.
Flowable formulations often require the use of differing concentrations of polymers depending upon the particular application intended. However, typical biodegradable polymers do not function well at widely variant concentrations in flowable delivery systems.
Consequently, there is a need for a method and composition which provides a biodegradable, polymer system that functions at widely different concentrations of polymer. Specifically, there is a need for a method and composition for a pharmaceutical system that can be used to provide implants of all kinds and also to provide controlled delivery systems.
These and other needs are met by the present invention, which is directed to a flowable composition suitable for use in medical applications. The present invention is also directed to the use of branched biodegradable biocompatible thermoplastic polymers as in situ and ex vivo solid matrices, and as delivery systems. The in situ and ex vivo implants as well as the delivery systems are produced by solidification of the flowable composition through its contact with aqueous medium, body fluid or water. The ex vivo implants are formed outside the body and are used as solid devices. They include, for example, microcapsules, microparticles, single body implants, sutures, surgical clips, staples, and stents.
The flowable composition is a solution or dispersion of a branched, biocompatible, biodegradable thermoplastic polymer or copolymer that is at least substantially water-insoluble and an organic solvent that is biocompatible and is at least slightly soluble in aqueous medium, water or body fluid. Once the flowable composition is placed into a substrate such as a body or aqueous medium, the polymer coagulates or solidifies into a solid matrix. The placement of the flowable composition can be anywhere within the body, including soft tissue such as muscle or fat, hard tissue such as bone, or a cavity such as the periodontal, oral, vaginal, rectal, nasal, or a pocket such as a periodontal pocket or the cul-de-sac of the eye.
In applications in which the flowable composition is used for controlled drug release, a biologically active agent is added to the composition. The biologically active agent is dissolved or dispersed in the composition of branched, biocompatible, biodegradable thermoplastic polymer and organic solvent to form a solution, suspension or dispersion. When this pharmaceutical composition is contacted with an aqueous medium, with a body fluid or with water, a solid polymer-bioactive agent matrix is formed.
Rate modifying agents to control the rate of release of the bioactive agent relative to the solid matrix without the additive can be included. Preservatives, homogenization agents, surfactants, colorants, fillers, and excipients can also be included.
Several advantages are achieved with the flowable composition of the invention compared with other systems. The flowable composition may be injected via syringe and needle into a body while it is in flowable form and will form in situ a solid biodegradable matrix. The need to form an incision is eliminated, and the implant will assume the shape of its cavity. A drug releasing implant may be provided by adding a biologically active agent to the flowable composition system prior to injection. Once the implant is formed, it will release the bioactive agent to the body over a period of time and will also biodegrade. The so-called burst effect or initial release of bioactive agent can be controlled with the flowable composition because high concentrations of polymer can be used in the flowable composition. Further, the same bioactive agent release profile as provided by implants from linear polymer compositions is achieved.
The invention also relates to solid articles for medical applications that are formed from the flowable compositions. Solid articles such as microcapsules, microparticles, monolithic implants, fasteners, medical devices, and controlled drug release systems are produced by ex vivo solidification of the flowable composition. The solid articles are then utilized within a body by, for example, suturing, clipping, insertion, injection, incision, inhalation and the like. When used as surgical clips, sutures, and pins, the solid articles provide needed support in medical applications. When used as drug release implants, these solid articles provide the controlled release of a bioactive agent.